Down syndrome, typically caused by a meiotic nondisjunction event resulting in trisomy 21, characteristically presents with intellectual disability, characteristic facial features and is often associated with congenital heart disease and increased risk of early-onset Alzheimer’s disease.
Description
Down Syndrome, also known as Trisomy 21, is a genetic disorder and the most common chromosomal anomaly in humans. It results from the presence of an extra copy of chromosome 21 and is characterised by intellectual disability, distinct facial features, and various congenital anomalies.
Pathogenesis
Down Syndrome occurs due to a chromosomal abnormality, specifically, the presence of three copies of chromosome 21 (trisomy 21) instead of the usual two. The additional genetic material interferes with normal development and function, leading to the manifestations of Down Syndrome.
- Meiotic nondisjunction (~95% cases) – Failure of a chromosome pair to separate during meiosis. Parents are normal in all respects. Correlation with maternal age suggests the extra chromosome is of maternal origin.
- Mosaicism (less common) – Only some cells have the extra chromosome 21, resulting in a mixture of cells with 46 or 47 chromosomes, resulting from mitotic nondisjunction of chromosome 21 during an early stage of embryogenesis.
- Robertsonian translocation (rare) – Extrachromosomal material derives from the presence of a Robertsonian translocation of the long arm of chromosome 21 to another acrocentric chromosome (e.g. 22 or 14).
Subtypes
Three subtypes of Down Syndrome exist:
- Standard Trisomy 21: The most common form, where every cell in the body has an extra copy of chromosome 21.
- Mosaic Down Syndrome: A less common form where only some cells have the extra chromosome 21.
- Robertsonian Translocation: The rarest form where the extra chromosome 21 is attached to another chromosome.
Epidemiology, Risk Factors & Associations
- Down Syndrome is the most common chromosomal disorder (1 in every 700 live births).
- Maternal age (> 35 years of age) is the most significant risk factor (e.g. 1 in 1,250 at age 25 vs 1 in 100 at age 40).
- In cases of Robertsonian translocation and mosaic Down syndrome, maternal age is of no importance.
- Possible association with mutation of the non-Hsa21 CRELD1 gene.
- Associated medical conditions include congenital heart defects, early-onset Alzheimer’s disease, leukaemia, and immune disorders.
- Risk decreases with gestational age because about 30% of affected foetuses die between the 12th and 40th week of pregnancy.
Clinical Features
- Characteristic facial features (upslanting palpebral fissures, flattened nasal bridge, small ears).
- Intellectual disability and delayed developmental milestones.
- Hypotonia and joint hypermobility.
- Congenital heart disease, often atrioventricular septal defects.
Cardiovascular
Congenital heart defects affect ~40% of patients.
- Atrioventricular septal defect – most common cardiac defect in Down syndrome, up to 40% of patients
- Ventricular septal defect – 2nd most common cardiac defect, up to 32% of patients
- Secundum atrial defects – 10%
- Tetralogy of Fallot – 6%
- Isolated PDA – 4%
Gastrointestinal
- Hirschsprung disease – 2%
- Coeliac disease
- Oesophageal and duodenal atresia
- Gastroesophageal reflux disorder, chronic constipation, intermittent diarrhoea
Haematological
- Neutrophilia – 80%
- Thrombocytopaenia – 66%
- Polycythaemia – 34%
Neurological
- Hypotonia – a Hallmark of babies with Down syndrome
- Seizures – tonic-clonic or myoclonic
- Alzheimer’s Dementia – early-onset, 50 – 70% of patients by age of 60
- Lennox-Gestaut syndrome – usually late onset and associated with reflex seizures along with an increased rate of EEG abnormalities
Endocrinological
- Thyroid gland dysfunction – most commonly associated endocrinological disorder.
- Congenital hypothyroidism
- Primary hypogonadism
- Girls – delayed menarche or adrenarche
- Boys – cryptorchidism, ambiguous genitalia, micropenis, small testes, low sperm count, scanty growth of axillary and pubic hair
- Short stature – insulin-like growth factors said to be responsible for the delay in skeletal maturation and short stature
Complications
- Increased risk of developing Alzheimer’s disease.
- Increased susceptibility to infections.
- Higher risk of leukaemia and testicular cancer.
Pathological Features
Histopathology
- Macroscopic: Characteristic facial features, congenital heart defects, gastrointestinal malformations, and other physical abnormalities.
- Microscopic: Characteristic changes in brain tissue (e.g., reduced volume, particularly in the frontal lobe, hippocampus, and cerebellum).
Serology
- Increased nuchal translucency on prenatal ultrasound (<3.5 mm is normal)
Biochemistry
- Altered levels of specific serum markers during pregnancy can suggest Down Syndrome, such as low PAPP-A and high free β-HCG.
- First trimester screening (performed between 10 and 14 weeks of gestation). The markers used for the risk calculation are 2 serum markers:
- PAPP-A – Low levels (<0.5 MoM, multiple of median) associated with increased risk for Down syndrome (and trisomy 18)
- Free β-hCG – High levels (>2.0 MoM) associated with increased risk of Down syndrome (decreased risk in trisomy 13 and 18).1
Radiological Features
General Features
- Characteristically demonstrates craniofacial abnormalities and heart defects.
CT
- Non-contrast: Can identify skeletal abnormalities and craniofacial features.
MRI
- Can demonstrate reduced brain volume and altered brain morphology.
Antenatal US
First trimester
- Increased nuchal translucency (measured between 10 and 13+6 weeks): Subcutaneous non-septated fluid seen on sagittal image of the foetal neck measuring > 3 mm in thickness
- Reversal of A-wave in ductus venosus
- Tricuspid regurgitation
- Absent nasal bone
Second-trimester
- Increased nuchal fold thickness of ≥ 6 mm is abnormal on a routine morphology ultrasound performed at 18-22 weeks.
- Cystic hygroma
Soft markers in order of likelihood:
- AVSD
- Ventriculomegaly
- Increased nuchal fold
- Absent or hypoplastic nasal bone
- Aberrant right subclavian artery
- Echogenic bowel – Non-specific. Echogenicity of bowel must be greater than bone to be abnormal. Focal echogenicity is more worrisome than diffuse.
- Mild hydronephrosis – Follow-up required to exclude obstructive cause.
- Intracardiac echogenic focus – Echogenic to bone. Usually within ventricle.
- Short humerus and femur
Diagnosis
Diagnosis can be prenatally through screening tests (ultrasound and maternal blood tests) and diagnostic tests (amniocentesis or chorionic villus sampling). Postnatally, diagnosis is based on characteristic clinical features and confirmed with genetic testing (karyotyping).
- Amniocentesis should not be performed before 16 weeks due to the higher risk of miscarriage (2% higher) and talipes equinovarus (1.5% higher) compared to second-trimester tissue sampling.
- CVS should not be performed before 11 weeks due to associated foetal transverse limb abnormalities, micrognathia and microglossia.
Differential Diagnosis
- Other chromosomal disorders with thickened nuchal fold:
- Patau syndrome (trisomy 13) – Holoprosencephaly
- Edwards syndrome (trisomy 18) – Choroid plexus cysts
- Turner syndrome
- Congenital heart disease
- Noonan’s syndrome
- Klippel-Feil syndrome
- Zellweger syndrome
- Cumming syndrome
- Robert syndrome 7
- normal variant (rare <1%)
- Cystic hygroma
- Hydrops
- An abnormally thickened nuchal fold or even a cystic hygroma may resolve, especially toward the third trimester; however, the risk of karyotypic abnormalities is not reduced.
- Other causes of echogenic bowel
- Infection, cystic fibrosis, placental insufficiency, intraamniotic bleed
- Bowel anomaly (atresias, ischaemia, rupture)
Management
Management is supportive and multidisciplinary, including early intervention services, speech therapy, occupational therapy, and physical therapy. Medical management of associated conditions, such as heart defects and thyroid dysfunction, is also critical.
References